435

synthesis and/or release of NO from cultured vascular endothelial cells.9 Endotoxin and its endogenous mediators can inhibit coronary vasodilator responses to agents that depend on increased synthesis of endothelium-derived NO; hence, the use of NO synthase inhibitors in this setting could induce coronary vasoconstriction and nominally restrict myocardial perfusion at best or provoke myocardial ischaemia at worst."’ This might explain the fall in cardiac index in one of Petros and colleagues patients.1 Although The Lancet editorial accompanying the paper by Petros et al implies that NO synthase inhibitors produced "beneficial cardiovascular effects" in the two patients, a fall in cardiac index would not be beneficial during sepsis, especially if accompanied by (or due to) an increase in peripheral vascular resistance and its attendant increase in cardiac workload. In view of the complex pharmacodynamic spectrum of drugs that inhibit NO synthase, we do not support further clinical trials in sepsis until animal studies have been done to disclose any adverse actions of these agents on perfusion of the coronary vasculature and other vital oxidative tissues. Departments of Anesthesiology and Internal Medicine, Washington University School of Medicine

RICHARD S. HOTCHKISS IRENE E. KARL

Department of Physiology, University of Missouri

JANET L. PARKER

Department of Veterinary Biomedical Sciences,

University of Missouri, Columbia, Missouri 65211, USA

H. RICHARD ADAMS

1. Moncada S, Higgs EA. Endogenous nitric oxide: physiology, pathology, and clinical relevance. Eur J Clin Invest 1991; 21: 361-74. 2. Hutcheson IR, Whittle B Jr, Boughton-Smith NK. Role of nitric oxide in maintaining vascular integrity in endotoxin-induced intestinal damage in the rat. Br J Pharmacol 1990; 101: 815-20. 3. Billiar TR, Curran RD, Harbrecht BG, Stuehr DJ, Demetris AJ, Simmons RL. Modulation of nitrogen oxide synthesis in vivo: NG-monomethyl-L-arginine inhibits endotoxin-induced nitrite/nitrate biosynthesis while promoting hepatic damage. J Leukoc Biol 1990; 48: 565-69 4. Faule KJ, Rossaint R, Keitel M, et al. Successful treatment of severe adult respiratory distress syndrome with nitric oxide: the first three patients. Presented at Second International Meeting on the Biology of Nitric Oxide (London, October, 1991). 5. Durante W, Schini VB, Scott-Burden T, et al Platelet inhibition by an L-arginine derived substance released by IL-I&bgr;-trcared vascular smooth muscle cells. Am J Physiol 1991; 261: H2024-H2030. 6. Nathan CF, Hibbs JB. Role of nitric oxide synthesis in macrophage antimicrobial activity. Curr Opin Immunol 1991; 3:65-70. 7 Madden HP, Breslin RJ, Wasserkrug HL, Efron BAG, Barbul A Stimulation of T cell immunity by arginine enhances survival in peritonitis. J Surg Res 1988; 44: 658-63. 8. Klabunde RE, Ritger RC. NG-monomethyl-L-arginine (NMMA) restores arterial blood pressure but reduces cardiac output in a canine model of endotoxic shock. Biochem Biophys Res Comm 1991; 178: 1135-40 9. Myers PR, Wright TF, Tanner MA, Adams HR. Endothelium-derived relaxing factor and nitric oxide production in cultured endothelial cells: direct inhibition by E coli endotoxin. Am J Physiol (in press) 10 Parker JL, Keller RS, DeFily DV, Laughlin MH, Novotny MJ, Adams HR. Coronary vascular smooth muscle function in E coli endotoxemia in dogs. Am J Physiol 1991; 260 (Heart Circ Physiol 29): H832-H841.

SIR,—To add to the two patients described by Dr Petros and colleagues, we would like to report a case of septic shock in a patient with severe hypotension and multiple organ failure who was successfully treated with 700 mg NG-monomethyl-L-arginine (NMMA). Less than 3 min after intravenous injection ofNMMA the blood pressure was normal and a continuous infusion of noradrenaline 25 pg/min could be stopped. A 29-year-old man was admitted to intensive care with necrotising pancreatitis. From admission the patient was on ventilatory support. Eleven abdominal surgical interventions were necessary and a splenic abscess was treated by splenectomy. The patient was on haemofiltration for 54 days and episodes of septicaemia were treated with antibiotics. From day 90 he improved. Haemofiltration was stopped on that day, and renal function returned to normal. The patient was still artificially ventilated but he could communicate again and started to exercise. On day 109 Pseudomonas aerugirwsa infection was diagnosed; this could be controlled with antibiotics. On day 119 the patient went into severe septic shock with hypotension due to septicaemia with a multiresistant coagulase-negative staphylococcus. He became anuric and haemofiltration had to be reintroduced. From day 119,

catecholamines had to be given in doses up to 25 ug/min noradrenaline, 400 ug/min dopamine, and 800 ug/min dobutamine to maintain the blood pressure. Despite antimicrobial treatment and massive volume substitution leading to a positive liquid balance of 32 litres in the previous 11 days, the patient deteriorated on day 123. Again, extensive volume substitution was necessary to maintain a systolic blood pressure around 100 mm Hg and a fatal outcome seemed likely. In this desperate setting, and knowing that NMMA had been approved for use in healthy volunteers, we decided to administer this agent, and the father of the unconscious patient

agreed. 700 mg NMMA (Sigma Chemicals) corresponding to 7 mg/kg body weight was given in 3 min by intravenous injection. Immediately after the injection the infusion of noradrenaline could be stopped and the blood pressure remained stable for about 25 min. His mean blood pressure then fell again below 85 mm Hg and noradrenaline had to be readminstered, at a dose of 14 ug/min. Subsequently, the dose of noradrenaline could be gradually reduced and 24 h after NMMA was given, it was stopped. Heart rate

(110-117/min) and central venous pressure were stable before, during, and after NMMA treatment. No side-effects of NMMA recorded. For 12 days thereafter, he was haemodynamically stable without catecholamines or haemofiltration being required. Further haemodynamic data are not available because a pulmonary catheter could not be inserted due to central venous obstruction as a consequence of the long stay in the intensive care unit and the number of catheters that had previously been inserted and removed. This experience strongly supports that of Petros et al and shows that the NO-synthase inhibitor, NMMA, may be successful in the treatment of severe hypotension in septic shock. were

STEPHANOS GEROULANOS

JULIAN SCHILLING METIN CAKMAKCI University Hospital Zurich,

HANS H. JUNG

CH-8091 Zurich, Switzerland

FELIX LARGIADER

Dissection of vertebral artery after cervical trauma

SIR,-Dissection of the vertebral artery has been described after trauma received during chiropractic manipulations,’ seizures,2 attempted strangulation,3playing softball, heavy lifting,4 yoga, bowhunting, neck hyperextension, atlantoaxial dislocation, sudden head turning, and fitness exercises.s Symptoms can arise immediately after trauma, but commonly are delayed from several hours to a few days.6 We report an unusual cause of vertebral artery cervical

dissection. A 33-year-old woman had abrupt onset of headache. Computed tomography of the head was normal and she was treated with analgesics. She awoke the next day with dysequilibrium, nausea, dysphagia, and slurred speech. Magnetic resonance imaging (MRI) of the head showed infarction of the left superior cerebellum and small infarctions of the left medial inferior temporal lobe and deep white matter of the right occipital lobe. She was admitted and left-sided ataxia, slight flattening of the left nasolabial fold, and dysarthria were noted. Cerebral angiography showed occlusion of the left vertebral artery; all other extracranial and intracranial vessels were normal. MRI angiography confirmed the total occlusion of the vertebral artery from C5 to the basilar artery. These findings were most consistent with dissection of the vertebral artery. Echocardiography and transoesophageal echocardiography were

normal,

as

were

laboratory

tests,

including erythrocyte

sedimentation rate, antinuclear antibodies, rheumatoid factor, complement levels, lupus anticoagulant, and antiphospholipid antibodies, and lumbar puncture results. On further questioning, the patient stated that four days before onset of headache she attended a fair where she rode an amusement ride called "the scrambler". This ride inflicted spinning motions as well as violent changes in direction on the participants. Her head was shaken in several linear and torsional directions. On completion of the ride, she felt disoriented and was asked by the attendent whether she was all right. She had generalised neck pain for several days afterwards.

436

We suggest that our patient had a dissection of the vertebral artery due to the violent neck movements associated with the scrambler. Although our patient anticipated temporary dysequilibrium and nausea from the scrambler, she had not thought that these might be longlasting effects. This very rare complication of amusement park rides might be prevented by avoiding excessive neck movements. JAMES BOWEN Pacific Medical Center, JOHN PATZ Division of Neurology, JAMES BAILEY Seattle WA 98144, USA, KAI HANSEN and University of Washington, Seattle 1. Frumkin L, Baloh R.

Wallenberg’s syndrome following neck manipulation. Neurology

1990; 40: 611-15.

Young C, Chadwick D, Humphrey P. Extracranial vertebral artery dissection following tonic clonic seizure. J Neurol Neurosurg Psychiatry 1991; 54: 365-66. 3. Biller J, Hingtgen W, Adams H, et al. Cervicocephalic arterial dissection. Arch Neurol 1986; 43: 1234-38. 4. Katirji M, Reinmuth O, Latchaw R. Stroke due to vertebral artery injury. Arch Neurol 1985; 42: 242-48. 5. Pryse-Phillips W. Infarction of the medulla and cervical cord after fitness exercises. 2.

Stroke 1989; 20: 292-94. 6. Hinse P, Thie A, Lachenmayer L. Dissection of the extracranial vertebral artery: report of four cases and review of the literature. J Neurol Neurosurg Psychiatry 1991; 54: 863-69.

Pulmonary hypertension and

therapy was described after fenfluramine ingestion for several months.3 Dexfenfluramine is thought to have few side-effects (sedation, lethargy, and dry mouth in the short term4 and no extra risks during long-term therapys). Fenfluramine and dexfenfluramine are related to amphetamine, and both sympathomimetic and serotoninergic effects of the pulmonary vascular system are to be expected. Serotonin was responsible for the development of pulmonary hypertension in animal studies with anorectic drugs.6 Apart from two cases reported to the French Centre for drug control pulmonary hypertension associated with dexfenfluramine has not been recorded. In the fatal case reported here the evidence suggests that the sequence of dexfenfluramine intake, followed by a stay at moderate altitude, and subsequent pregnancy triggered irreversible primary pulmonary hypertension. The indication for dexfenfluramine has been questioned in a Lancet editoriaF because the drug adds little to other weight-reducing measures. Even if anorectic agents only rarely cause or contribute to the development of pulmonary hypertension, it seems reasonable to advise that they are not tried until all other measures have been exhausted. PETER G. ATANASSOFF BRANKO M. WEISS Department of Anaesthesiology, E. R. SCHMID University Hospital of Zurich, CH-8091 Zurich, Switzerland M. TORNIC

dexfenfluramine SiR,—Dexfenfluramine is used as adjuvant therapy for obesity. Pulmonary hypertension has been described with D, Lfenfluramine but not with the pure D-isomer, dexfenfluramine. A 30-year-old woman was admitted to hospital at 34 weeks’ gestation. She had no history of cardiac or respiratory disease. She had taken dexfenfluramine for six months between July, 1989, and March, 1990, and stopped after reaching her desired body weight. In March, 1990, shortly before she became pregnant, and while on holiday 800 m above sea level, the patient complained of reduced exercise tolerance with dyspnoea and tiredness on the slightest exertion. Echocardiography before the onset of pregnancy had revealed a slightly dilated right ventricle. The patient was admitted because of early uterine contractions but examination revealed severe dyspnoea and a respiratory rate of 28/min. There was loud pulmonary component of the heart sound and a pansystolic murmur at the left sternal border compatible with tricuspid regurgitation. She had a regular heart rate of 96/min, her blood pressure was 100/70 mm Hg, and she had increased jugular venous pressure. Arterial blood gas analysis was pH 7-53, pCO 2-79 kPa, p02 8-86 kPa, and an arterial oxygen saturation of 95% on room air. Electrocardiography demonstrated sinus rhythm and an incomplete right-bundle-branch block, and on chest radiography moderate enlargement of the right ventricle was seen. Electrocardiography disclosed advanced dilatation of the right ventricle. The pulmonary artery pressure was 84 mm Hg above right atrial pressure, and there was mild tricuspid valve incompetence. A ventilation-perfusion scan did not demonstrate pulmonary embolism. Elective caesarean section was done under epidural anaesthesia, which was haemodynamically well tolerated. Pressures (mm Hg) during the procedure were: mean pulmonary artery (PAP) 44-59, mean systemic arterial 56-85, central venous 12-18, and pulmonary capillary wedge 15-25. Cardiac index ranged from 1.56 to 2.13 1/min per m2. Calculated pulmonary vascular resistance (PVR) was 542—858 dyn/s per cm5. Postoperatively her pulmonary hypertension worsened and did not respond to prostaglandin E1 or diuretic therapy (PAP 52-77 mm Hg, PVR 551-1231 dyn/s per cms). On day 3 she had a cardiac arrest and on day 4 she died in right ventricular failure. Necropsy revealed right heart hypertrophy and

plexogenic pulmonary arteriopathy. Primary pulmonary hypertension predominantly affects women of childbearing age and often gets worse during pregnancy.1 A relation between anorectic drugs and pulmonary hypertension has been known for a long time and three cases of pulmonary hypertension in women taking fenfluramine have been described. In two patients, pulmonary hypertension resolved upon withdrawal of the drug, but it reappeared in one of them after reingestion of fenflurarnine .2 Another case of pulmonary hypertension resistant to

W, Braunwald E. Pulmonary hypertension. In: Braunwald E, ed. Heart disease, 3rd ed. Philadelphia: Saunders, 1988: 793-818. 2. Douglas JG, Munro JF, Kitchin AH, Muir AL, Proudfoot AT. Pulmonary hypertension and fenfluramine. Br Med J 1981; 283: 881-83. 3. McMurray J, Bloomfield P, Miller HC. Irreversible pulmonary hypertension after 1. Grossman

with fenfluramine. Br Med J 1986; 292: 239-40 B. Therapeutic use of dexfenfluramine in obesity. In: Bender AF, Brookes LJ, eds. Body weight control: the physiology, clinical treatment and prevention of obesity. Edinburgh: Churchill Livingstone, 1987; 280-85. 5. Gotestam RG, Dahl CB Fenfluramine and drug addiction. In: Bender AF, Brookes LJ, eds. Body weight control: the physiology, clinical treatment and prevention of obesity. Edinburgh: Churchill Livingstone, 1987: 271-79. 6. Seiler KU, Tamm G, Wassermann O. Effects of anorectic drugs and serotonin (5-HT) on the vascular system of isolated rat lungs. Naunyn-Schmidebergs Arch Pharmacol 1974; 282: suppl R92. 7. Editorial. Dexfenfluramine. Lancet 1991; 337: 1315-16. treatment

4.

Guy-Grand

SIR,-Drug-induced pulmonary hypertension has been associated with phenformin, but anorectic drugs such as aminorex and fenfluraminel-5 have been more frequently involved. We report reversible pulmonary hypertension caused by dexfenfluramine. A 26-year-old woman was referred to our hospital in October, 1990, with pulmonary hypertension, and no significant medical history before January, 1990. She had taken dexfenfluramine from December, 1989, to January, 1990, at a daily dose of 15-30 mg. She had never taken any other medication. She experienced exertional dyspnoea and palpitations toward the end of January, 1990. Because nasal plastic surgery was scheduled, she underwent a medical examination in February, 1990. An electrocardiogram showed signs of cor pulmonale; both pulmonary arteries were enlarged on standard chest radiography but computed angiography showed no pulmonary embolism. The surgery was done in April, 1990. Because her dyspnoea had worsened, she was re-examined in July, 1990. She had a pulmonary regurgitant murmur and a split second heart sound; chest radiography was normal; an electrocardiogram still showed signs of cor pulmonale. Catheterisation studies pointed to primary pulmonary hypertension, at which point the patient was referred here but she did not consult us until October, when she no longer had either dyspnoea or palpitations, and no abnormality of the respiratory or cardiovascular systems was found during physical examination. Chest radiography showed a mild enlargement of pulmonary arteries. Electrocardiogram, arterial blood gases, and lung function were normal, as was a perfusion lung scan, conventional pulmonary angiography, and phlebocavography. Catheterisation studies (cardiac output 7-41/min in October) were: Pulmonary

artery

Date Cafe

a/e/y

July

82/27(50) 34/5(14)

October Pressures (mm Hg)

as

Capillary Right wece )/e/7ff/ct//af 5 85/0

wedge ventricular 5

32/0

systolic/diastolic (mean)

Use of aminorex in Germany,

Switzerland, and Austria between 1967 and 1970 was followed by a 20-fold increase in the incidence of